This nonprovisional application claims priorty under 35 U.S.C. xc2xa7 119(a) on Patent Application No. 01118098.6 filed in China on May 18, 2001, which is herein incorporated by reference.
The present invention relates to a method of producing analgesia in a mammal experiencing pain, comprising administering to the mammal a composition comprising a synergistically effective analgesic combination of an opioid analgesic agent and a compound that binds to the SS1 or SS2 subunit of a sodium channel in a pharmaceutically suitable vehicle.
According to U.S. Pat. No. 6,150,524, opioid analgesics such as morphine are the most powerful analgesics for treating severe chronic and acute pain. An example of chronic pain is the pain experienced by cancer patients. An example of acute pain is the pain experienced after operations. The pain relieving activity of opioid analgesics includes a depressive effect on the central nervous system. The analgesic activity of opioid analgesics such as morphine and deltorphin II can be mediated via different opioid receptors, for example, viaxcexc-opioid and xcex4-opioid receptors. Opioid analgesics are invaluable for the treatment of severe acute or chronic pain as, for example, may occur in bone degenerative diseases and cancer conditions. They are easy to administer and they provide effective pain relief in most patients. Due to the excellent overall tolerability of opioids, the doses of morphine and other strong opioids can be increased to relatively high levels.
The opioids used for treating such pain are indeed highly effective but have a number of unpleasant and/or undesirable side effects (e.g. a short duration of activity, respiratory depression, nausea, constipation, diuresis and euphoria and they are also addictive). In some patients, particularly in the chronically ill, the opioid side effects make it impossible to continuously administer sufficiently high dosages to adequately control pain over the needed period of time. There are also some pain conditions that do not sufficiently respond to opioid pain treatment alone. Therefore, there is a constant need for improved opioid containing analgesic combinations with increased analgesic activity which comprise opioid and non-opioid analgesically active agents and which offer the possibility of reducing the opioid dose needed for efficient pain relief and thereby also reducing the opioid side effects that might result from the otherwise required higher dosages.
Recently, Hartmann (U.S. Pat. No. 6,150,524) and Nagase (U.S. Pat. No. 6,177,438) have discovered morphine derivatives through modifying the structure of morphine so as to reduce the adverse effects associated with the use of morphine. The results based upon animal studies, however, are still insufficient to support pharmaceutical use in humans with acceptable safety and efficacy.
On the other hand, sodium channel blocking compounds that bind to the SS1 or SS2 subunit of a sodium channel, particularly tetrodotoxin and saxitoxin, are found to possess a potent analgesic property (U.S. patent application Ser. No. 09/695,053). Tetrodotoxin is effective on all severe chronic pains. Tetrodotoxin is capable of providing analgesia in a mammal experiencing acute or chronic pain.
In one embodiment, tetrodotoxin (TTX) was found to be about 3,000 times more analgesically potent than morphine. Moreover, TTX does not produce addiction. Furthermore, trials in humans indicate that TTX also provides a duration of action much longer than morphine. TTX provides significant analgesia for pain from chemical stimulation. However, a larger dose appears to be necessary for suppressing pain induced by heat. In studies of use of TTX to treat addiction, experiments suggest a steep dose-toxicity curve for TTX. Therefore, there is a need to improve safety by reducing the TTX dose needed for efficient pain relief.
Fairbanks (U.S. Pat. No. 6,204,271) introduced co-administration of an opioid analgesic agent and moxonidine as a non-opioid agent for producing synergistic analgesia in mammals, hoping to provide a reduced propensity for causing undesirable side effects. Moxonidine is known to be an imidazoline/xcex12-adrenergic (I1/xcex12-AR) receptor agonist and is clinically used in antihypertensive medications. Monoxidine is reported to have analgesic activity, but is not comparable to TTX, which is potent and provides long duration of relief in cancer patients. TTX is also non-addictive as shown through studies in a variety of animals.
The present invention is related to producing analgesia in mammals, in particular in humans, by co-administering synergistically effective amounts of (1) a sodium channel blocking compound that specifically binds to the SS1 or SS2 subunit of a sodium channel, such as tetrodotoxin or saxitoxin or analogs thereof; and (2) an opioid analgesic agent. The present invention further pertains to analgesic pharmaceutical compositions comprising synergistically effective amounts of a sodium channel-blocking compound that specifically binds to the SS1 or SS2 subunit of a sodium channel and an opioid analgesic agent.
An object of this invention is to provide a potent analgesic composition containing a long-acting analgesic sodium channel-blocking compound that binds to the SS1 or SS2 subunit of a sodium channel, and an opioid analgesic agent, with a reduced propensity for causing undesirable adverse effects.
It is also an object of the invention to provide a non-addictive sodium channel blocker with analgesic activity showing synergy with the analgesic activity of the opioid, and to provide analgesic compositions comprising an opioid analgesic agent, such as morphine and its derivatives, and such a synergistically effective non-addictive sodium channel blocker which allows reducing the amount of the opioid necessary to achieve effective pain treatment.
It is further an object of the invention to present a method for producing analgesia induced by opioids or sodium channel blockers that binds to the SS1 or SS2 subunit in larger mammals, particularly in humans, whereby undesirable side effects of acute and chronic administration of strong opioids and said sodium channel blockers are reduced.